Temozolamide is the first drug approved by the United States Food and Drug Administration in over 50 years for the treatment of brain tumors. It is an imidazole tetrazinone compound and has demonstrated clinical efficacy in the treatment of high grade gliomas and malignant melanoma. Resistance to temozolamide therapy has been reported to develop due to the activity of poly (ADP-ribose) polymerase (Tentori et al. 1997. Mol. Pharmacol. 52:249-258; Wedge et al. 1996. Br. J. Cancer 74:1030-1036). Like most chemotherapeutic agents, the dose-limiting toxicity of the drug is related to myelosuppression.
Thymidine is a naturally occurring nucleoside metabolite which preferentially kills neoplastic cells in vitro and induces partial regression of a wide variety of human tumor xenografts, including malignant glioma (O""Dwyer, P. J. et al. 1987. Cancer Res. 47:3911-3919; Cohen, J. D. et al. 1989. Cancer Res. 49:5805-5809; Cohen, J. D. et al. 1990. J. Neurooncol. 9:1-8). The mechanism of action of this nucleotide is related to the intracellular triphosphorylation that occurs which leads to triphosphate modulation of ribonucleotide reductase, resulting in deoxycytidine starvation, an increase in deoxyguanosine triphosphate, and an inhibition of poly (ADP-ribose) polymerase. Inhibition of this key DNA repair enzyme results in cessation of DNA synthesis, inhibition of DNA repair, and cell death (O""Dwyer, P. J. et al. 1987. Cancer Res. 47:3911-3919). 
Prolonged infusions with thymidine of up to 30 days in patients with leukemia have resulted in anti-cancer activity but also significant myelotoxicity (Kufe, D. W. et al. 1980. Blood 55:580-589). Shorter infusions of high dose thymidine, however, have been shown to be effective and free of the myelosuppressive activity that is usually dose-limiting (Cohen, J. D. et al. 1990. J. Neurooncol. 9:1-8). 
Recent studies have examined the combined treatment with a known chemotherapeutic agent, carboplatin, and thymidine. The combination therapy was initiated based on studies in cells that showed that inhibition of poly (ADP-ribose) polymerase activity results in enhancement of the anti-neoplastic activity of carboplatin (Cohen, J. D. et al. 1989. Cancer Res. 49:5805-5809; Cohen, J. D. et al. 1990. J. Neurooncol. 9:1-8). The sensitization of cells to the effects of carboplatin increased as thymidine exposure increased, up to 16 hours, until the effect reached a plateau. In initial clinical studies, the pharmacokinetics of the thymidine-carboplatin interaction were studied. Thymidine was shown not to affect the pharmacokinetics or protein binding of carboplatin (Robins, H. I. et al. 1999. J. Clin. Oncol. 17:2922-2931). Three of the six patients in the study, being treated for recurrent malignant glioma, showed at least partial disease remission. In addition, thymidine was shown to protect against dose-limiting carboplatin myelotoxicity. Following completion of the Phase I study with thymidine and carboplatin in combination therapy, a Phase II recurrent high-grade glioma study was initiated (Robins, H. I. et al. 2000. Proceedings of the American Society for Clinical Oncology 19:166a). initiated (Robins, H. I. et al. 2000. Proceedings of the American Society for Clinical Oncology 19:166a). Consistent with the results of the Phase I study, thymidine was myeloprotective, resulting in a minimal need for dose reduction due to myelotoxicity.
There continues to be a need for effective treatment regimens in a variety of cancers, including recurrent brain cancer, where the combination of therapeutics results in either an enhanced clinical efficacy and/or a reduced occurrence of adverse side effects which would allow for administration of higher doses of effective chemotherapeutics.
An object of the present invention is a method for treating cancer which comprises administration of a combination of thymidine and temozolamide.
Another object of the present invention is a method for reducing dose-limiting toxicity of a chemotherapeutic drug which comprises administration of thymidine in combination with the chemotherapeutic, temozolamide.
Yet another object of the present invention is a method for increasing the efficacy of a chemotherapeutic drug in the treatment of cancer which comprises administration of thymidine in combination with the chemotherapeutic, temozolamide.